The human toll of hypertension (HTN) is staggering, and effective preventive measures are needed. Experimental studies suggest that inadequate vitamin D and I-3 fatty acid (FA) levels may be involved in the pathogenesis of HTN through multiple biological mechanisms. Observational studies have shown inverse associations of plasma 25-hydroxyvitamin D (25[OH]D) levels and dietary I-3 FA intake with blood pressure (BP) and HTN. Small intervention trials of vitamin D and fish oil rich in I-3 FA suggest possible BP-lowering effects; however, larger trials using adequately high doses of vitamin D and I-3 FA for the primary prevention of HTN are lacking. The VITamin D and OmegA-3 TriaL (VITAL), an NIH-supported, large, randomized, double-blind, placebo-controlled, 2x2 factorial trial, will test 2000 IU/day of vitamin D (as vitamin D3 [cholecalciferol]) and 1 g/day of marine I-3 FA (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) supplements on incident cardiovascular disease and cancer in 20,000 multiethnic men and women with 5 years of treatment and follow-up. VITAL provides an optimal cost-effective setting to examine the effects of both interventions on changes in BP and incident HTN. Further, as this project would begin in parallel with enrollment into the parent VITAL trial, pre-randomization assessments of BP and biomarkers will be possible. In this proposed ancillary study, we will recruit a representative subcohort of 1,000 VITAL participants without baseline HTN from 5 major US metropolitan areas to conduct home-based examinations at baseline and 2 years follow-up through Examination Management Services, Inc (EMSI). We will obtain 24-hour ambulatory BP (ABP), fasting bloods, 24-hour urines, and other clinical assessments in this EMSI subcohort. We will also ascertain incident HTN cases in the overall VITAL trial. We will test the following hypotheses: (1) whether vitamin D and fish oil supplementation lowers 24-hour ABP compared to placebo in the EMSI subcohort of 1,000 participants; (2) whether vitamin D and fish oil supplementation reduces the risk of incident HTN compared to placebo among all randomized VITAL participants without baseline HTN; and (3) whether vitamin D and fish oil supplementation favorably changes HTN-related biomarkers that are putative mechanistic mediators linking vitamin D and I-3 FAs with HTN compared to placebo. This proposed study will provide definitive evidence to support or refute the potential preventive roles of vitamin D and I-3 FA on BP and the development of HTN. PUBLIC HEALTH RELEVANCE: Prior research suggests that vitamin D and fish oil (which contains nutrients called omega-3 fatty acids) might help lower blood pressure and prevent hypertension; however, this remains unproven because large and more definitive research studies have not been done. This proposed study will be a large-scale and long-term randomized trial that will demonstrate whether taking vitamin D or fish oil supplements can lower someone's blood pressure or prevent the development of hypertension. Because high blood pressure is responsible for one out of every six deaths in the United States, the results of this study could possibly improve the health of many people.